Kidney biopsy for suspected MGRS in a diabetic patient

Dysproteinemiashard

A 68-year-old woman with long-standing type 2 diabetes complicated by neuropathy and hypertension is evaluated for proteinuria and increased serum creatinine. Her medications include glipizide, valsartan, amlodipine, atorvastatin, and aspirin. She reports no changes to her medication regimen and does not use over-the-counter medications, herbal supplements, or NSAIDs. She feels well and reports no problems with urination, changes in weight, fever, rash, arthralgias, or cardiopulmonary symptoms. BP is 142/60 mm Hg, heart rate is 75/min, and body mass index is 29 kg/m². On examination, she has retinal cotton wool spots and 1+ edema of her lower extremities bilaterally. Laboratory data (6 months ago, current): WBC count 8000/µL, 7300 (reference 4000–11,000); hemoglobin 12.6 g/dL, 12.4 (12–16); platelet count 230,000/µL, 263,000 (150,000–450,000); potassium 4.5 mEq/L, 4.7 (3.5–5.0); creatinine 1.1 mg/dL, 1.9 (0.5–1.1); calcium 9.0 mg/dL, 9.2 (8.6–10.2); albumin 3.9 g/dL, 3.8 (3.5–5.5); total protein 7.1 g/dL, 6.8 (5.5–9.0); hemoglobin A1C 7.2%, 7.3 (4.0–5.6); urine protein-to-creatinine ratio 0.8 mg/mg, 2.5 (<0.2); free kappa light chain 30 mg/L (3.3–19.4); free lambda light chain 7 mg/L (5.7–26.3); free kappa-to-free lambda light chain ratio 4.28 (0.26–1.65). Urinalysis demonstrates 3+ protein but is otherwise normal. Urine microscopy demonstrates occasional granular casts. Serum protein electrophoresis (SPEP) and immunofixation are normal. Urine protein electrophoresis (UPEP) and immunofixation reveal 2.5 g protein/24 h consisting of 90% albumin with no Bence-Jones proteins. Kidney ultrasound demonstrates bilateral 11-cm kidneys with mildly increased echogenicity. The postvoid bladder volume is 25 mL. Which ONE of the following is the MOST appropriate next step?

  1. A.Prescribe canagliflozin
  2. B.Perform kidney biopsyCorrect
  3. C.Measure antinuclear antibodies
  4. D.Perform bone marrow biopsy

Explanation

The most appropriate next step for this patient with worsening proteinuria and kidney function is to perform a kidney biopsy. Although this patient has evidence of diabetes-related microvascular disease and may well have diabetic kidney disease, this diagnosis would be unlikely to explain the relatively rapid worsening of proteinuria and eGFR. In this patient, the SPEP and UPEP with immunofixation (SIFE and UIFE, respectively) were negative for a monoclonal protein, but the serum free light chain ratio was abnormal, which is suspicious for a monoclonal gammopathy of renal significance (MGRS). The serum free light chain assay, which individually measures kappa and lambda light chains, is the most sensitive test to diagnose MGRS. In one study, only 85% of patients with monoclonal immunoglobulin deposition disease (MIDD) had a positive SPEP, SIFE, UPEP, or UIFE. All patients, however, had an abnormal serum free light chain assay. A wide spectrum of kidney diseases can be induced by monoclonal immunoglobulins, including some glomerular lesions that may mimic diabetic nephropathy. In these cases, IF and EM are essential to establishing the diagnosis. Amyloidosis and C3 glomerulopathy, for example, can be induced by light chains and present with heavy albuminuria rather than Bence-Jones proteinuria. Although bone marrow biopsy could reveal a plasma cell or lymphocyte dyscrasia, demonstration of myeloma or a lymphocytic lymphoma would be unexpected in the absence of more overt laboratory abnormalities or cytopenias. Measurement of antinuclear antibodies, and/or other studies such as anti-phospholipase A2 receptor antibodies, complement levels, and hepatitis serologies, among others, would be reasonable to obtain in the investigation of proteinuria and decreased kidney function. However, even if results were abnormal, kidney biopsy would still be necessary to determine whether an MGRS is present. Optimizing the medical management of this patient's diabetes by adding a sodium-glucose transporter type 2 inhibitor, such as canagliflozin, or a mineralocorticoid receptor blocker, such as spironolactone or finerenone, are adjunctive treatments that can reduce proteinuria and preserve kidney function in patients with diabetic kidney disease. However, these measures would not obviate the need for a kidney biopsy in this case.

Why each option

A.
Canagliflozin reduces proteinuria and slows diabetic kidney disease, but it would not obviate a biopsy when an abnormal light chain ratio suggests MGRS.
B.
Correct. Rapidly rising proteinuria and creatinine with a kappa-to-lambda ratio of 4.28 suggest MGRS, which only kidney biopsy with IF and EM can establish.
C.
ANA and other serologies are reasonable in proteinuria workup, but even abnormal results would not remove the need for biopsy to assess MGRS.
D.
Bone marrow biopsy may reveal a clone, but without cytopenias or a detectable M-protein myeloma is unlikely, and it cannot define kidney pathology.

Reference: Leung N, Nat Rev Nephrol 2019 (IKMG consensus on the evaluation of monoclonal gammopathy of renal significance); KDIGO 2022 Clinical Practice Guideline for Diabetes Management in CKD

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